Meningitis without Rash after Reactivation of Varicella Vaccine Strain in a 12-Year-Old Immunocompetent Boy.

Acute neurologic complications from Varicella-Zoster-Virus reactivation occur in both immunocompromised and immunocompetent patients. In this report, we describe a case of a previously healthy immunocompetent boy who had received two doses of varicella vaccine at 1 and 4 years. At the age of 12 he developed acute aseptic meningitis caused by vaccine-type varicella-zoster-virus without concomitant skin eruptions. VZV-vaccine strain DNA was detected in the cerebrospinal fluid. The patient made a full recovery after receiving intravenous acyclovir therapy. This disease course documents another case of a VZV vaccine-associated meningitis without development of a rash, i.e., a form of VZV infection manifesting as "zoster sine herpete".

Limitations of Nasal Nitric Oxide Measurement for Diagnosis of Primary Ciliary Dyskinesia with Normal Ultrastructure.

Rationale: Primary ciliary dyskinesia (PCD) is a heterogeneous, multisystem disorder characterized by defective ciliary beating. Diagnostic guidelines of the American Thoracic Society and European Respiratory Society recommend measurement of nasal nitric oxide (nNO) for PCD diagnosis. Several studies demonstrated low nNO production rates in PCD individuals, but underlying causes remain elusive. Objectives: To determine nNO production rates in a well-characterized PCD cohort, including subgroup analyses with regard to ultrastructural and ciliary beating phenotypes. Methods: This study included 301 individuals assessed according to European Respiratory Society guidelines. Diagnostic cutoffs for nNO production rates for this study cohort and subgroups with normal and abnormal ultrastructure were determined. Diagnostic accuracy was also tested for the widely used 77 nl/min cutoff in this study cohort. The relationship between nNO production rates and ciliary beat frequencies (CBFs) was evaluated. Results: The study cohort comprised 180 individuals with definite PCD diagnosis, including 160 individuals with genetic diagnosis, 16 individuals with probable PCD diagnosis, and 105 disease controls. The 77 nl/min nNO cutoff showed a test sensitivity of 0.92 and specificity of 0.86. Test sensitivity was lower (0.85) in the subgroup of 47 PCD individuals with normal ultrastructure compared with 133 PCD individuals with abnormal ultrastructure (0.95). The optimal diagnostic cutoff for the nNO production rate for the whole study cohort was 69.8 nl/min (sensitivity, 0.92; specificity, 0.89); however, it was 107.8 nl/min (sensitivity, 0.89; specificity, 0.78) for the subgroup of PCD with normal ultrastructure. PCD individuals with normal ultrastructure compared with abnormal ultrastructure showed higher ciliary motility. Consistently, PCD individuals with higher CBFs showed higher nNO production rates. In addition, laterality defects occurred less frequently in PCD with normal ultrastructure. Conclusions: Measurements of nNO below the widely used 77 nl/min cutoff are less sensitive in detecting PCD individuals with normal ultrastructure. Our findings indicate that higher nNO production in this subgroup with a higher cutoff for the nNO production rate (107.8 nl/min) and higher residual ciliary motility is dependent on the underlying molecular PCD defect. Higher nNO production rates, higher residual CBFs, and the lower prevalence of laterality defects hamper diagnosis of PCD with normal ultrastructure. Adjusting the cutoff of nNO production rate to 107.8 nl/min might promote diagnosing PCD with normal ultrastructure.

TRAPγ-CDG shows asymmetric glycosylation and an effect on processing of proteins required in higher organisms.

Newly synthesised glycoproteins enter the rough endoplasmic reticulum through a translocation pore. The translocon associated protein (TRAP) complex is located close to the pore. In a patient with a homozygous start codon variant in TRAPγ (SSR3), absence of TRAPγ causes disruption of the TRAP complex, impairs protein translocation into the endoplasmic reticulum and affects transport, for example, into the brush-border membrane. Furthermore, we observed an unbalanced non-occupancy of N-glycosylation sites. The major clinical features are intrauterine growth retardation, facial dysmorphism, congenital diarrhoea, failure to thrive, pulmonary disease and severe psychomotor disability.

CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module.

Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45-/- mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module.

Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Use of maintenance antibiotic therapy with the macrolide azithromycin is increasing in a number of chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD. METHODS: The Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial was a multicentre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial done at 6 European PCD clinics (tertiary paediatric care centres and university hospitals in Denmark, Germany, Netherlands, Switzerland, and UK). Patients with a confirmed diagnosis of PCD, aged 7-50 years old, and predicted FEV1 greater than 40% were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 mg or 500 mg as tablets according to bodyweight (

SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal nitric oxide measurement, analysis of ciliary beating, transmission electron microscopy (TEM), and/or genetic testing. In most genetic PCD variants, laterality defects can occur. However, it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition. Mutations in HYDIN are known to cause CP defects, but the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure. We have previously shown that several types of PCD can be diagnosed via immunofluorescence (IF) microscopy analyses. Here, using IF microscopy, we demonstrated that in individuals with PCD and CP defects, the CP-associated protein SPEF2 is absent in HYDIN-mutant cells, revealing its dependence on functional HYDIN. Next, we performed IF analyses of SPEF2 in respiratory cells from 189 individuals with suspected PCD and situs solitus. Forty-one of the 189 individuals had undetectable SPEF2 and were subjected to a genetic analysis, which revealed one novel loss-of-function mutation in SPEF2 and three reported and 13 novel HYDIN mutations in 15 individuals. The remaining 25 individuals are good candidates for new, as-yet uncharacterized PCD variants that affect the CP apparatus. SPEF2 mutations have been associated with male infertility but have not previously been identified to cause PCD. We identified a mutation of SPEF2 that is causative for PCD with a CP defect. We conclude that SPEF2 IF analyses can facilitate the detection of CP defects and evaluation of the pathogenicity of HYDIN variants, thus aiding the molecular diagnosis of CP defects.

Active perinatal care of preterm infants in the German Neonatal Network.

OBJECTIVE: To determine if survival rates of preterm infants receiving active perinatal care improve over time. DESIGN: The German Neonatal Network is a cohort study of preterm infants with birth weight <1500 g. All eligible infants receiving active perinatal care are registered. We analysed data of patients discharged between 2011 and 2016. SETTING: 43 German level III neonatal intensive care units (NICUs). PATIENTS: 8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care. INTERVENTIONS: Participating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25-P75) and low (

Temporary Tracheal Stenting After Pulmonary Artery Sling Repair in a Newborn.

Pulmonary artery sling (PAS) is a rare disease frequently associated with severe malacia and stenosis of the trachea. We present a two-day-old newborn that underwent urgent surgery for PAS and needed prolonged respiratory support afterward. Temporary airway stenting above the level of the tracheal bifurcation was performed five days after surgery to overcome severe airway obstruction caused by tracheomalacia and laceration of the tracheal mucosa after diagnostic bronchoscopy. Two days after the procedure, the child could be extubated and after two weeks the stent was removed without complications. Temporary tracheal stenting after PAS repair can be an effective therapeutic strategy in newborns with tracheal obstruction and allows timely weaning from ventilator support.

Acinetobacter baumannii Is a Risk Factor for Lower Respiratory Tract Infections in Children and Adolescents With a Tracheostomy.

BACKGROUND: Lower respiratory tract infections (LRIs) are a major cause of hospitalization for children and adolescents with a tracheostomy. The aim of this study was to identify risk factors for LRI. METHODS: In this retrospective study, we assessed the number of LRI and hospitalizations for LRI from 2004 to 2014 at the University Hospital Muenster Pediatric Department. We analyzed associations between LRI and clinical findings, and we cultured pathogens in tracheal aspirates (TAs) during noninfection periods. Univariable and multivariable negative, binomial regression analyses were applied to identify associations between possible risk factors and LRI. RESULTS: Seventy-eight patients had 148 LRI, of which 99 were treated in hospital. The median number of LRI per year was 0.4. Six-hundred thirteen pathogens were detected in 315 specimens; Staphylococcus aureus (22.5%), Pseudomonas aeruginosa (14.8%) and Haemophilus influenzae (6.2%) were most frequently detected. Acinetobacter baumannii is an independent risk factor for LRI (rate ratio, 1.792; P = 0.030) and hospital admissions for LRI (rate ratio, 1.917; P = 0.011). CONCLUSIONS: Children with a tracheostomy have frequent LRI. A. baumannii but not P. aeruginosa or S. aureus in TA is a risk factor for LRI in children with a long-term tracheostomy. This supports repetitive culture of TA for microbiologic workup to identify children and adolescents with an increased risk for LRI.

Prevalence and course of disease after lung resection in primary ciliary dyskinesia: a cohort & nested case-control study.

BACKGROUND: Lung resection is a controversial and understudied therapeutic modality in Primary Ciliary Dyskinesia (PCD). We assessed the prevalence of lung resection in PCD across countries and compared disease course in lobectomised and non-lobectomised patients. METHODS: In the international iPCD cohort, we identified lobectomised and non-lobectomised age and sex-matched PCD patients and compared their characteristics, lung function and BMI cross-sectionally and longitudinally. RESULTS: Among 2896 patients in the iPCD cohort, 163 from 20 centers (15 countries) underwent lung resection (5.6%). Among adult patients, prevalence of lung resection was 8.9%, demonstrating wide variation among countries. Compared to the rest of the iPCD cohort, lobectomised patients were more often females, older at diagnosis, and more often had situs solitus. In about half of the cases (45.6%) lung resection was performed before presentation to specialized PCD centers for diagnostic work-up. Compared to controls (n = 197), lobectomised patients had lower FVC z-scores (- 2.41 vs - 1.35, p = 0.0001) and FEV1 z-scores (- 2.79 vs - 1.99, p = 0.003) at their first post-lung resection assessment. After surgery, lung function continued to decline at a faster rate in lobectomised patients compared to controls (FVC z-score slope: - 0.037/year Vs - 0.009/year, p = 0.047 and FEV1 z-score slope: - 0.052/year Vs - 0.033/year, p = 0.235), although difference did not reach statistical significance for FEV1. Within cases, females and patients with multiple lobe resections had lower lung function. CONCLUSIONS: Prevalence of lung resection in PCD varies widely between countries, is often performed before PCD diagnosis and overall is more frequent in patients with delayed diagnosis. After lung resection, compared to controls most lobectomised patients have poorer and continuing decline of lung function despite lung resection. Further studies benefiting from prospective data collection are needed to confirm these findings.

Comparison of Nocturnal Cough Analysis in Healthy Subjects and in Patients with Cystic Fibrosis and Primary Ciliary Dyskinesia: A Prospective Observational Study.

BACKGROUND: Cough is a key symptom in patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). OBJECTIVE: The study objectives were to test whether cough is related to parameters reflecting their disease severity and whether CF and PCD differ in cough frequency. METHODS: In this prospective observational study, we used a microphone-based monitoring system (LEOSound® Monitor) to count the coughs in healthy subjects (HS) and in stable patients with CF and PCD (25 subjects per group) on 2 consecutive nights. RESULTS: The median number of coughs/h in the HS, CF, and PCD groups was 0.0, 1.3, and 0.5 on the first night and 0.0, 2.3, and 0.2 on the second night, respectively. Patients with CF and PCD coughed more than HS (p < 0.001 and p = 0.009, respectively) and CF patients coughed more than PCD patients (p = 0.023). A multivariable mixed model analysis revealed forced expiratory volume in 1 s as an independent risk factor for increased cough frequency in patients. The reliability for repeated measurements was higher for cough epochs/h than for coughs/h (intraclass correlation coefficient: 0.75 and 0.49, respectively). CONCLUSIONS: Patients with CF cough more than patients with PCD. The cough frequency in CF and PCD is associated with parameters reflecting disease severity. Cough frequency is a possible endpoint in clinical trials and cough epochs/h may be more useful than coughs/h.

Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects.

Dysfunction of motile monocilia, altering the leftward flow at the embryonic node essential for determination of left-right body asymmetry, is a major cause of laterality defects. Laterality defects are also often associated with reduced mucociliary clearance caused by defective multiple motile cilia of the airway and are responsible for destructive airway disease. Outer dynein arms (ODAs) are essential for ciliary beat generation, and human respiratory cilia contain different ODA heavy chains (HCs): the panaxonemally distributed γ-HC DNAH5, proximally located ß-HC DNAH11 (defining ODA type 1), and the distally localized ß-HC DNAH9 (defining ODA type 2). Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction. Consistent with the observed subtle respiratory phenotype, high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia. DNAH9-deficient cilia also lack other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating an essential role of DNAH9 for distal axonemal assembly of ODAs type 2. Yeast two-hybrid and co-immunoprecipitation analyses indicate interaction of DNAH9 with the ODA components DNAH5 and DNAI2 as well as the ODA-docking complex component CCDC114. We further show that during ciliogenesis of respiratory cilia, first proximally located DNAH11 and then distally located DNAH9 is assembled in the axoneme. We propose that the ß-HC paralogs DNAH9 and DNAH11 achieved specific functional roles for the distinct axonemal compartments during evolution with human DNAH9 function matching that of ancient ß-HCs such as that of the unicellular Chlamydomonas reinhardtii.

Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways.

Cilia are organelles specialized for movement and signaling. To infer when during evolution signaling pathways became associated with cilia, we characterized the proteomes of cilia from sea urchins, sea anemones, and choanoflagellates. We identified 437 high-confidence ciliary candidate proteins conserved in mammals and discovered that Hedgehog and G-protein-coupled receptor pathways were linked to cilia before the origin of bilateria and transient receptor potential (TRP) channels before the origin of animals. We demonstrated that candidates not previously implicated in ciliary biology localized to cilia and further investigated ENKUR, a TRP channel-interacting protein identified in the cilia of all three organisms. ENKUR localizes to motile cilia and is required for patterning the left-right axis in vertebrates. Moreover, mutation of ENKUR causes situs inversus in humans. Thus, proteomic profiling of cilia from diverse eukaryotes defines a conserved ciliary proteome, reveals ancient connections to signaling, and uncovers a ciliary protein that underlies development and human disease.

Should transmission electron microscopy and ultrastructural cilia evaluation remain part of the diagnostic work-up for primary ciliary dyskinesia?

The diagnostic work-up for primary ciliary dyskinesia (PCD) traditionally includes ciliary ultrastructural assessment using transmission electron microscopy (TEM). However, the identification of genetic variants of PCD that are missed by TEM, along with the development of novel diagnostic modalities for PCD that allow structural evaluation of cilia, such as immunofluorescence analysis and the increased availability of genetic testing, calls into questioning the contemporary role of TEM in the diagnostic work-up for PCD. In this manuscript, we describe the evidence for and against the use of TEM in PCD diagnosis, in light of recent developments of PCD.

Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies.

Primary ciliary dyskinesia (PCD) is an orphan disease (MIM 244400), autosomal recessive inherited, characterized by motile ciliary dysfunction. The estimated prevalence of PCD is 1:10,000 to 1:20,000 live-born children, but true prevalence could be even higher. PCD is characterized by chronic upper and lower respiratory tract disease, infertility/ectopic pregnancy, and situs anomalies, that occur in ≈50% of PCD patients (Kartagener syndrome), and these may be associated with congenital heart abnormalities. Most patients report a daily year-round wet cough or nose congestion starting in the first year of life. Daily wet cough, associated with recurrent infections exacerbations, results in the development of chronic suppurative lung disease, with localized-to-diffuse bronchiectasis. No diagnostic test is perfect for confirming PCD. Diagnosis can be challenging and relies on a combination of clinical data, nasal nitric oxide levels plus cilia ultrastructure and function analysis. Adjunctive tests include genetic analysis and repeated tests in ciliary culture specimens. There are currently 33 known genes associated with PCD and correlations between genotype and ultrastructural defects have been increasingly demonstrated. Comprehensive genetic testing may hopefully screen young infants before symptoms occur, thus improving survival. Recent surprising advances in PCD genetic designed a novel approach called "gene editing" to restore gene function and normalize ciliary motility, opening up new avenues for treating PCD. Currently, there are no data from randomized clinical trials to support any specific treatment, thus, management strategies are usually extrapolated from cystic fibrosis. The goal of treatment is to prevent exacerbations, slowing the progression of lung disease. The therapeutic mainstay includes airway clearance maneuvers mainly with nebulized hypertonic saline and chest physiotherapy, and prompt and aggressive administration of antibiotics. Standardized care at specialized centers using a multidisciplinary approach that imposes surveillance of lung function and of airway biofilm composition likely improves patients' outcome. Pediatricians, neonatologists, pulmonologists, and ENT surgeons should maintain high awareness of PCD and refer patients to the specialized center before sustained irreversible lung damage develops. The recent creation of a network of PCD clinical centers, focusing on improving diagnosis and treatment, will hopefully help to improve care and knowledge of PCD patients.

Chest physiotherapy can affect the lung clearance index in cystic fibrosis patients.

OBJECTIVES: The lung clearance index (LCI) is determined by multiple-breath washout lung function (MBW). It is increasingly used as an endpoint in clinical trials. Chest physiotherapy (CP) is part of routine cystic fibrosis (CF) care. Whether the LCI is useful in detecting short-term treatment effects of CP has not been sufficiently investigated. We assessed the short-term influence of CP with highly standardized high-frequency chest wall oscillation (HFCWO) on the LCI in CF patients. METHODS: In this randomized controlled study, the LCI was obtained in 20 CF patients (7-34 years) hospitalized for infective pulmonary exacerbation prior to and immediately after a single treatment of HFCWO. Twenty-one control group CF patients (7-51 years) received no treatment. We calculated the coefficient of repeatability (CR) to estimate the clinical relevance of possible treatment effects. RESULTS: HFCWO improved (ie, decreased) the LCI by a median of 0.9 (range -0.45; 3.47; P = 0.002); the LCI decreased in 15 of 20 intervention group patients. In five patients the decrease in LCI exceeded the CR (2.15), indicating a clinically relevant treatment effect; in five patients the LCI increased but did not exceed the CR. The LCI did not change significantly in the control group patients. CONCLUSIONS: HFCWO can have a short-term decreasing effect on the LCI, but the treatment response is heterogeneous. In future trials using LCI as an endpoint, the timing of CP in relation to MBW should be considered a possible bias.

Mutations in PIH1D3 Cause X-Linked Primary Ciliary Dyskinesia with Outer and Inner Dynein Arm Defects.

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right body axis disturbance. Here we report maternally inherited and de novo mutations in PIH1D3 in four men affected with PCD. PIH1D3 is located on the X chromosome and is involved in the preassembly of both outer (ODA) and inner (IDA) dynein arms of cilia and sperm flagella. Loss-of-function mutations in PIH1D3 lead to absent ODAs and reduced to absent IDAs, causing ciliary and flagellar immotility. Further, PIH1D3 interacts and co-precipitates with cytoplasmic ODA/IDA assembly factors DNAAF2 and DNAAF4. This result has clinical and genetic counseling implications for genetically unsolved male case subjects with a classic PCD phenotype that lack additional phenotypes such as intellectual disability or retinitis pigmentosa.

The international primary ciliary dyskinesia cohort (iPCD Cohort): methods and first results.

Data on primary ciliary dyskinesia (PCD) epidemiology is scarce and published studies are characterised by low numbers. In the framework of the European Union project BESTCILIA we aimed to combine all available datasets in a retrospective international PCD cohort (iPCD Cohort).We identified eligible datasets by performing a systematic review of published studies containing clinical information on PCD, and by contacting members of past and current European Respiratory Society Task Forces on PCD. We compared the contents of the datasets, clarified definitions and pooled them in a standardised format.As of April 2016 the iPCD Cohort includes data on 3013 patients from 18 countries. It includes data on diagnostic evaluations, symptoms, lung function, growth and treatments. Longitudinal data are currently available for 542 patients. The extent of clinical details per patient varies between centres. More than 50% of patients have a definite PCD diagnosis based on recent guidelines. Children aged 10-19 years are the largest age group, followed by younger children (≤9 years) and young adults (20-29 years).This is the largest observational PCD dataset available to date. It will allow us to answer pertinent questions on clinical phenotype, disease severity, prognosis and effect of treatments, and to investigate genotype-phenotype correlations.

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia.

The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia.

Collecting clinical data in primary ciliary dyskinesia- challenges and opportunities.

Rationale: Primary ciliary dyskinesia (PCD) is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility. Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research. Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback. Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire. Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research.